Is CIROP p.Phe456del (c.1364TCT[1]) pathogenic?

CIROP p.Phe456del (c.1364TCT[1]) is classified Pathogenic in CIROP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-15). Very rare (popmax 0.00104%, nfe); Associated with heterotaxy, visceral, 12, autosomal.

What condition is associated with CIROP p.Phe456del (c.1364TCT[1])?

CIROP p.Phe456del (c.1364TCT[1]) is associated with heterotaxy, visceral, 12, autosomal (ClinVar).

How common is CIROP p.Phe456del (c.1364TCT[1]) in the general population?

CIROP p.Phe456del (c.1364TCT[1]) is very rare (popmax 0.00104%, nfe) (gnomAD).

CIROP p.Phe456del

c.1364TCT[1] · rs1392604380 · VCV1335922

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00104%, nfe)

Conditions

heterotaxy, visceral, 12, autosomal

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 2.2, phastCons 1
Overall
CADD	17.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00104% European (non-Finnish) · 4/385,000 alleles

Filtering AF 0.000343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000164%

Overall 0.000569% 4/702,732 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIROP
Protein: p.Phe456del
Coding: c.1364TCT[1]
MANE Select: NM_001354640
dbSNP: rs1392604380
Type: Microsatellite
Location: chr14:23101852 (GRCh38)
Structure: AlphaFold pLDDT 73.73
Residue 456: a UniProt-annotated variant site (in htx12); a UniProt-annotated variant site (in htx12; uncertain significance)

Full CIROP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

heterotaxy, visceral, 12, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIROP p.Arg101fs Likely pathogenic ★ same condition
CIROP p.Gln528Ter Likely pathogenic ★ same condition
CIROP p.Leu444fs Likely pathogenic ★ same condition
CIROP p.Arg22Ter Conflicting classifications of pathogenicity ★ same condition
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same condition
CIROP p.Gly511Glu Uncertain significance ★ ⚠ same condition
CIROP p.Ser31Phe Conflicting classifications of pathogenicity ★ ⚠ same condition
CIROP p.Tyr68Cys Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cirop-p-phe456del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown